Peripheral arterial disease (PAD) affects approximately 8-12 million adults in the United States, and despite its significant impact on morbidity and mortality, a definitive medical therapy to improve perfusion in the ischemic hind limb is lacking. In response to tissue ischemia, a complex cascade of events leads to sprouting of new blood vessels from existing capillaries in the vicinity of ischemic tissue to form new blood vessels. This process of angiogenesis is an adaptive mechanism to promote blood supply to the ischemic tissue. Therapeutic angiogenesis, the stimulation of growth of new blood vessels distal to the site of occlusion, is an investigational therapeutic strategy to create a medical bypass to the ischemic limb and help improve perfusion in the ischemic tissue. A multitude of angiogenic growth factors have been exhaustively studied in both pre-clinical models of PAD and in clinical patients with PAD. Despite initial success in pre-clinical settings, most growth factors have uncertain final clinical outcomes. This necessitates a better understanding of regulation of gene expression following tissue ischemia.
In the past decade, micro-RNAs have emerged as strong endogenous regulators of gene expression, particularly important in disease/injury states. Micro-RNAs (miRs) are 16-25 nucleotide non-coding RNAs that are endogenous regulators of gene expression, particularly in disease/injury states. Micro-RNAs typically work by targeting mRNA degradation or by direct translational repression, and they can regulate a single gene or entire pathways (1, 2). Some micro-RNAs play crucial roles in developmental vasculogenesis (3) and in tumor angiogenesis (4-7). However, information on the role of micro-RNAs in ischemia-induced angiogenesis such as in myocardial ischemia and PAD is limited. Bonauer et al. showed that systemically delivered antagomirs against miR-92a enhanced perfusion recovery in a mouse model of PAD (8). Selection of miR-92a was based on the known role of the miR-17˜92-cluster in angiogenesis, and its high level of expression in human umbilical vein endothelial cells (HUVEC) (8). Grundman et al. showed that inhibiting miR-100 enhanced perfusion recovery in the same hind-limb ischemia (HLI) model (9). Selection of miR-100 was based on its down-regulation in ischemic hind limb in a single strain of mice (C57B1/6J) (9). Finally, Yin et al. selected miR-15a based on its known role in regulation of Bcl-2 and its induction in oxygen-glucose deprived cerebral endothelial cells, and miR-15a knockdown improved angiogenesis in HLI (10).
There is a long felt need in the art for compositions and methods useful for enhancing endothelial cell and myocyte survival, for inducing angiogenesis, for treating ischemia, and for treating diseases, conditions, and disorders such as PAD. The present invention satisfies these needs.